1. Field of the Invention
The field of the invention is crystal forms of a known compound, 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethyl-amino)-2-pyridinyl]piperazine monomethanesulfonate salt, which is a pharmaceutical useful in treating individuals who are HIV positive.
2. Description of the Related Art
It is known to those skilled in the art that solids including pharmaceuticals often have more than one crystal form and this is known as polymorphism. Numerous examples are cited in the standard references of solid state properties of pharmaceuticals, Byrn, S. R., Solid-State Chemistry of Drugs, New Your, Academ. Press (1982); Kuhnert-Brandstatter, M., Thermomiscroscopy In The Analysis of Pharmaceuticals, New York, Pergamon Press (1971) and J. Pharm. Sci., 58, 911 (1969). Byrn states that, in general, polymorphs exhibit different physical characteristics including solubility and physical and chemical stability. It is important to note that there is no reliable method to predict the observable crystal structures of a given drug or to predict the existence of polymorphs with desirable physical properties.
U.S. Pat. No. 3,565,924 discloses and claims 25-hydroxycocalciferol (25-HCC) which is a solid. Even in view of this prior art the United States Patent Office allowed U.S. Pat. No. 3,833,622 to a novel crystal form 25-HCC hemihydrate.
U.S. Pat. No. 4,521,431 discloses forms 1 and 2 of ranitidine hydrochloride.
U.S. Pat. No. 4,504,657 claims xe2x80x9ccrystalline 7-[D-xcex1-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid monohydrate.
International Publication No. WO 91/09849 (EXAMPLE 105) discloses 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine. Antimicrobial Agents and Chemotherapy, 1127-31 (May 1993) discloses 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine free base. The Journal of Medicinal Chemistry, 36, 1505 (1993) discloses 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in the xe2x80x9cSxe2x80x9d crystal form.
Disclosed is 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt known as the xe2x80x9cSxe2x80x9d form with a powder X-ray diffraction spectrum of that set forth in the claims.
Also disclosed is 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt known as the xe2x80x9cTxe2x80x9d form with a powder X-ray diffraction spectrum of that set forth in the claims.
1-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl)-piperazine is known, see International Publication No. WO 91/09849 (EXAMPLE 105). 1-[5-Methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is also known, see Journal of Medicinal Chemistry, 36, 1505 (1993) and Antimicrobial Agents and Chemotherapy, 1127-31 (May 1993).
The xe2x80x9cSxe2x80x9d crystal form (also known as form VIII) of 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is produced by starting with 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in other than the xe2x80x9cSxe2x80x9d form and dissolving it in a dissolving solvent selected from the group consisting of methanol, ethanol, acetonitrile, dimethyl sulfoxide and dimethylformamide or mixture thereof; it is preferred that the dissolving solvent is methanol. When starting with the free amine, methylene chloride can be used as a co-dissolving solvent preferably with methanol, but alone will not appreciably dissolve the starting material. To the solution of the salt in the dissolving solvent is added a sufficient quantity of crystallizing solvent, or mixtures thereof, which is selected from the group consisting of acetone, acetonitrile, isopropanol, n-propanol, methyl t-butyl ether, toluene, ethyl acetate, n-propyl acetate, i-propyl acetate, tetrahydrofuran, toluene or any isomer of xylene, hexane or heptane; it is preferred that the crystallizing solvent be acetone. It is preferred to add a very small amount of the desired crystal form as it hastens crystallization of the desired xe2x80x9cSxe2x80x9d form. After the 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt crystallizes, it is filtered and dried as is known to those skilled in the art.
When the xe2x80x9cSxe2x80x9d crystal form of 1-[5-methanesulfonamidoindolyl-2-carbon-yl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is desired, it is preferred to dissolve the 1-[5-methanesulfonamidoindolyl-2-carbon-yl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in methanol to give a concentration of about 1 g of compound/5 ml of methanol. This mixture is then concentrated atmospherically to a concentration of about one molar by reflux. While maintaining reflux, acetone (about 4 ml/g of 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt) is added over a short period, for example five or ten minutes. At this point it is desirable and preferred to seed the crystallization with a small amount of the xe2x80x9cSxe2x80x9d crystal form. The mixture is stirred at reflux until crystallization occurs. The mixture can be filtered while hot or cooled.
An alternative procedure is to start with 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine free base and produce the methanesulfonic acid salt at the same time as the crystallization, see EXAMPLEs 2 and 8, which is the preferred method of practicing the invention on large scale. For small scale (laboratory or bench size) and infrequent runs the processes of EXAMPLEs 1, 4 and 6 are preferred.
When it is desired to start with the free base and acetonitrile as the dissolving solvent, at temperatures below 400 a solvated crystal form is produced. On drying, the acetonitrile is removed from the solid product and a desolvated crystal form results. When starting with the free base and methanol as the dissolving solvent and using isopropanol as the crystallizing solvent, none of the undesired crystal form that occurs with acetonitrile and low temperature occurs, but the crystals can agglomerate which can make drying more difficult. When acetone is used as the crystallizing solvent, the agglomeration problem does not occur.
The xe2x80x9cTxe2x80x9d crystal form (also known as form XI) of 1-[5-methanesulfonamidoindolyl-2-carbonyl]4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is produced by starting with 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in other than the xe2x80x9cTxe2x80x9d form and recrystallizing from a dissolving solvent (as identified above). The use of a crystallizing solvent (identified above) is optional. The xe2x80x9cTxe2x80x9d form of 1-(5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt can be produced from either the free base or a different crystal form of the mesylate salt as is described above for the xe2x80x9cSxe2x80x9d crystal form. For obtaining the xe2x80x9cTxe2x80x9d form it is preferred to have a concentration of about 1 g of compound/ml of dissolving solvent, especially when the dissolving solvent is methanol. When producing the xe2x80x9cTxe2x80x9d crystal form, it is preferred to seed the reaction mixture with previously obtained xe2x80x9cTxe2x80x9d crystal.
Both xe2x80x9cSxe2x80x9d and xe2x80x9cTxe2x80x9d forms of 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt are used in the same way as described for 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine in International Publication No. WO 91/09849. More specifically, the xe2x80x9cSxe2x80x9d and xe2x80x9cTxe2x80x9d forms of 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt are useful in the treatment of AIDS.
The term human retrovirus (HRV) indicates human immunodeficiency virus type I, or strains thereof apparent to one skilled in the art, which belong to the same viral families and which create similar physiological effects in humans as various human retroviruses.
Patients to be treated would include those individuals (1) infected with one or more than one strain of a human retrovirus as determined by the presence of either measurable viral antibody or antigen in the serum and (2) having either a symptomatic AIDS defining infection such as (a) disseminated histoplasmosis, (b) isopsoriasis, (c) bronchial and pulmonary candidiasis including pneumocystic pneumonia (d) non-Hodgkin""s lymphoma or (e) Kaposi""s sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/m3 in the peripheral blood. The xe2x80x9cSxe2x80x9d and xe2x80x9cTxe2x80x9d forms of 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt can be given orally. Suitable dosage forms include tablets, capsules, suspensions, solutions and elixirs. An effective amount is from about 0.1 to about 500 mg/kg/day. A typical unit dose for a 70 kg human would be from about 10 mg to about 2000 mg, preferably about 100 mg to about 1000 mg taken one to six times per day.
The exact dosage and frequency of administration depends on whether xe2x80x9cSxe2x80x9d or the xe2x80x9cTxe2x80x9d form of 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt is used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt in the patient""s blood and/or the patient""s response to the particular condition being treated.
Patients who are HIV positive but asymptomatic would typically be treated with lower oral doses (about 0.2 to about 100 mg/kg/day. ARC (AIDS-related complex) and AIDS patients would typically be treated with higher oral doses (about 1 to about 500 mg/kg/day).
The xe2x80x9cSxe2x80x9d and xe2x80x9cTxe2x80x9d forms of 1-[5-methanesulfonamidoindolyl-2-carbonyl]-4-[3-(1-methylethylamino)-2-pyridinyl]piperazine monomethanesulfonate salt of this invention can be be used in conjunction with other antiviral agents such as AZT.
The exact dosage and frequency of administration depends on the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of CD4 in the patient""s blood and/or the patient""s clinical response.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
All temperatures are in degrees Centigrade.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).